A) Vulvar Vestibulitis
Vulvar vestibulitis syndrome (herein "vulvar vestibulitis") is a subtype of vulvodynia.
Vulvodynia is a complex gynecologic syndrome characterized by unexplained vulvar pain, sexual dysfunction, and psychological disability. It is one of the most perplexing problems faced by the practicing gynecologist. Although the exact prevalence of vulvodynia is unknown, the condition is relatively common. In a vaginitis referral population symptoms are present in as many as 15-20% of the patients seen. It has been estimated that 11/2 million American women may suffer from some degree of vulvodynia. Vulvodynia can have multiple etiologies, and several subtypes have been recognized.
The most common subtype of vulvodynia is vulvar vestibulitis, which has been called "focal vulvitis" and "vestibular adenitis." Vulvar vestibulitis presents a constellation of symptoms involving and limited to the vulvar vestibule. The criteria for recognizing vulvar vestibulitis include: (1) pain on vestibular touch or attempted vaginal entry, (2) tenderness to Q-tip pressure localized within the vulvar vestibule, (3) physical findings confined to vestibular erythema of various degrees, and (4) an exclusion of other causes for vestibular erythema and tenderness, such as candidiasis (yeast infections) or herpes infections. Other symptoms include itching, swelling and excoriation.
The pain in vulvar vestibulitis may be described as sharp, burning, or a sensation of rawness. In severe cases, dyspareunia totally prohibits sexual intercourse. Pain may also be elicited on tampon insertion, biking, or wearing tight pants. The erythema may be diffuse or focal, and may be localized around the orifices of the vestibular glands or at the fourchette. In addition, patient symptoms may often include itching. Morbidities extend well beyond the local symptoms, with many women undergoing tremendous changes in psychosexual self-image, and can include profound adverse effects on marriages and other important relationships.
Vulvar vestibulitis may be acute or chronic. In one study, an arbitrary cutoff of three months of symptoms was used to distinguish between the acute and chronic forms (Marinoff and Turner, Am. J. Obstet. Gynecol. 165:1228-33, 1991). Most clinicians use an arbitrary cutoff of six months to distinguish between the acute and chronic forms. Several investigators have attempted to find a common histopathological aspect to vulvar vestibulitis, but have failed to do so.
Pyka et al. studied the histopathology of vulvar vestibulitis in specimens from 41 patients who had vulvar surgery for treatment of the syndrome (Int. J. Gynecol. Pathol. 7:249-57, 1988). They reported a mild to moderate mixed chronic inflammatory response. The infiltrate was characterized by lymphocytes and plasma cells, with only small numbers of polymorphonuclear leukocytes. Minor vestibular glands showed varying degrees of squamous metaplasia and were not affected by inflammatory cells. No fungi, gram-positive bacteria, mycobacteria, spirochetes, or Donovan bodies were detected. There was no evidence of an allergic phenomenon or an immediate hypersensitivity reaction, each of which would have exhibited characteristics histologic findings.
The causes of vulvar vestibulitis are multifactorial. Known and suspected causes of the acute form include fungal or bacterial infection (e.g. Candida, Trichomonas), chemical irritants (e.g. soaps, douches, sprays), therapeutic agents (e.g. antiseptics, suppositories, creams, 5-fluorouracil methods (e.g. cryosurgery, laser treatment), and allergic drug reactions. In the acute form, treatment of the presumed cause may lead to rapid relief.
Vulvar vestibulitis may become chronic if the cause becomes persistent or recurrent. Chronic vulvar vestibulitis may also persist long after all suspected causes have been treated. And many causes of chronic vulvar vestibulitis are of unknown etiology. Although no direct cause and effect relationship has been shown, it has been suggested that oxalates in the urine, altered vaginal pH, localized peripheral neuropathy, and subclinical viral infections can all contribute to the syndrome. A history of fungal infection is present in most patients who have vulvar vestibulitis, suggesting that recurrent yeast infections may somehow play a role in the initiation of the syndrome. It has been suggested that conditions such as recurrent candidiasis may lead to local changes in the vaginal immune system, including both Th1 and Th2 type responses (Fidel and Sobel, Clin. Microbiol. Reviews 9(3):335-48, 1996).
Because of its multiple causes, and its frequently unknown causes, vulvar vestibulitis can be very difficult to treat. Patients frequently suffer through a period of misdiagnosis, and may present with a long history of unsuccessful attempts at therapy.
B) Treatment of Vulvar Vestibulitis
The first-line therapy for vulvar vestibulitis is the treatment of its suspected causes. This includes the pharmacologic treatment of infections and the discontinued use of the irritants and therapeutic agents, local and systemic, that may contribute to the problem. Topical anesthetics, corticosteroids, and sex hormones may provide some symptomatic relief.
In many cases, treatment of the suspected causes does not lead to a cure. Further treatments may include dietary modifications, physical therapy and biofeedback, use of topical, oral, or injected therapeutic agents, or surgery. Unfortunately, no single treatment works in all patients. Moreover, many of these approaches involve complex medical procedures, significant costs, and/or undesirable side effects.
In the dietary approach, a low oxalate diet is combined with calcium citrate supplementation. One disadvantage to this approach is that it can be difficult to consistently modify eating habits. Another disadvantage is that the foods which must be avoided include those that are generally though to be important in a healthy diet (e.g. cruciferous vegetables).
Physical therapy and biofeedback, to strengthen the pelvic muscles and break the cycle of muscle spasm, may provide relief in some patients. This approach is very labor intensive and expensive, and does not always provide relief.
Topical therapeutic agents which have been used in the treatment of vulvar vestibulitis include corticosteroids, estrogen, progesterone, and capsaicin cream.
Oral therapeutic agents which have been used in the treatment of vulvar vestibulitis include isotretinoin, dapsone, acyclovir, and tricyclic anti-depressants such as amitriptyline. In addition to having variable therapeutic effects, each of these agents can cause undesirable side effects. Isotretinoin can cause mucocutaneous, gastrointestinal, cerebral, ocular and metabolic side effects, as well as severe fetal malformation in the event of pregnancy. Dapsone can cause anemia, jaundice, gastrointestinal distress, and weakness, and requires the monitoring of hemoglobin, hematocrit, and white cell count. Acyclovir can cause headaches and mild gastrointestinal upset. And the side effects of the tricyclic antidepressants include drowsiness, weight gain, and dry mouth.
Intralesional alpha-interferon injections may provide relief from vulvar vestibulitis in some patients.
Nyirjesy and Halpern have described a sequential treatment study, designed to assess the efficiency of medical (rather than surgical) management of vulvar vestibulitis, and to determine whether historical variables could be used to predict which treatments would be successful (Infectious Diseases in Obstetrics and Gynecology 3:193-97, 1995). Seventy-four patients were treated using a sequence of consecutive medical therapies: topical aqueous 4% lidocaine with intercourse, topical corticosteroid therapy, oral amitriptyline, topical low-dose 5-fluorouracil (5-FU) cream, intralesional alpha-interferon, and a low-oxalate diet in combination with oral calcium citrate. The patients were followed over 3-30 months. Forty-nine patients (66.2%) reported positive responses, including 18.1% of the patients who used lidocaine, 33.8% who used topical corticosteroids, 57.1% who used amitriptyline, 16.7% who used 5-FU, none who received interferon, and 50% who tried a low-oxalate diet. No historical variables were predictive of which therapies would have the most successful outcome.
Surgery is the treatment of choice for severe incapacitating cases of vulvar vestibulitis that do not respond to the more conservative treatments described above. Perineoplasty, also called vestibulectomy, is carried out under general anesthesia. An outer incision line is made from the periurethral glands on one side, along Hart's line, down into and including a good portion of the fourchette and back along Hart's line to the periurethral glands on the other side. An inner incision line is made behind the hymenal ring. The horseshoe-shaped tissue between these lines is excised, and the vagina is mobilized and advanced onto the perineum to cover the defect. Care must be taken to identify the bladder and rectum. Complications of surgery can include wound hematoma, dehiscence, uneven healing, and duct stenosis with cyst formation. At least 5-10% of patients are not cured even with surgery.
Superficial laser ablation of the vestibule has been used as an alternative to surgery, but in general the results have been disappointing. The procedure requires a prolonged healing time, and after treatment the symptoms are frequently the same or worse than before treatment.
There is a need for improved methods for treating vulvar vestibulitis, especially those cases of unknown etiology and those cases that fail to respond to the treatment of suspected causes.
C) Mast Cells
Mast cells, which are derived from bone marrow progenitors, play a role in immediate hypersensitivity and other inflammatory reactions by releasing a variety of chemical mediators upon activation. These mediators, some of which are stored as granules in the cytoplasm, include biogenic amines such as histamine, lipid mediators such as leukotrienes, prostaglandins, and platelet-activating factor, cytokines, and enzymes. Mast cells can be activated by crosslinking of surface IgE attached to FC.epsilon.RI, by chemokines, cytokines, neurotransmitters and other activating agents, or by local trauma.
Saban et al. reported high densities of mast cells in bladder biopsies from interstitial cystitis (an idiopathic inflammatory syndrome of the urogenital tract) subjects (Semin. Urol. IX:88-101, 1991). It has been speculated that the tissues involved in interstitial cystitis and vulvar vestibulitis may share a common embryologic origin and therefore be predisposed to similar pathological response (Fitzpatrick et al., Obstet. Gynecol. 81:860-62, 1993). Histopathological studies of specimens from vulvar vestibulitis subjects, however, report the presence of varying numbers of mast cells. Using a special toluidine blue staining, Pyka et al. found mast cells in only three of fourteen (21 %) cases of vulvar vestibulitis (Int. J. Gynecol. Pathol. 7:249-57, 1988). Chaim et al., in contrast, used a special Giemsa stain and identified large numbers of mast cells in sixteen of sixteen vulvar vestibulitis subjects undergoing surgical intervention (Eur. J. Obstetrics & Gynecol. And Reproductive Biol. 68:165-68, 1996). Chaim et al. speculated that pathways of mast cell activation at the bladder level may also be involved in the etiology of pure idiopathic vulvar vestibulitis. Chaim et al. also found mast cells in vulvar tissues of patients with vulvar displasia and suggested that mast cells may not be specific for vulvar vestibulitis syndrome.
D) Compounds Which Inhibit the Release of Mediators from Mast Cells
Immediate hypersensitivity reactions, including the release of mediators from mast cells, cause various allergic diseases in susceptible individuals. Compounds which inhibit the release of mediators from mast cells are said to "stabilize" mast cells, and are used for the treatment of human allergy. Various compounds, including cromolyn compounds, nedocromil compounds, and others, are known to inhibit the release of mediators from mast cells.
Cromolyn or cromoglycic acid (C.sub.23 H.sub.16 O.sub.11, 1,3-bis(2-carboxychromon-5-yloxy)-2-hydroxypropane), a chromone complex that inhibits the release of mediators from mast cells and blocks mast cell degranulation, has the following structure (I): ##STR1##
The disodium salt of cromolyn (C.sub.23 H.sub.14 Na.sub.2 O.sub.11, cromolyn sodium, disodium cromoglycate, sodium cromoglycate) is a water soluble, odorless, white, hydrated crystalline powder.
Cromolyn sodium, which inhibits the release of histamine and other mediators from mast cells that have been sensitized by specific antigens, is used pharmacologically as an antiasthmatic/antiallergic. Oral formulations of cromolyn sodium are used to treat the diarrhea, flushing, headaches, vomiting, urticaria, abdominal pain, nausea, and itching of mastocytosis, which is an accumulation of mast cells in the tissues. Opthalmic and nasal solutions of cromolyn sodium are used to treat the itching, redness, swelling, sneezing, tearing, and discharge of allergic conjunctivitis and allergic rhinitis. And inhalation aerosols of cromolyn sodium are used as prophylactic agents in the management of asthma.
Cromolyn sodium has been used to manage the symptoms of allergic vaginitis generally and seminal fluid hypersensitivity specifically. It has also been used in patients with vulvar intraepithelial neoplasia.
Allergic vaginitis includes IgE-mediated reactions to antigens in seminal fluid and to atmospheric allergens such as pollen. Allergic vaginitis is characterized by vaginal itching and burning pain or discomfort on coitus. It has been reported that cromolyn sodium solutions, used as a vaginal douche or injected intravaginally using a rubber ear syringe, can provide some relief from the symptoms of allergic vaginitis (Dworetzky and Galland, Am. J. Obstet. Gynecol. 161(6):1752-53, 1989).
Seminal fluid hypersensitivity is an allergic reaction to antigens in the seminal component of male ejaculate. Seminal fluid hypersensitivity is characterized by a spectrum of local and systemic hypersensitivity reactions, which can include postcoital vulvovaginal itching, swelling, redness, fixed cutaneous eruptions, burning, and pain, with or without the progression to systemic anaphylaxis. These hypersensitivity reactions can be prevented by avoiding contact with seminal fluid, through abstinence or the use of condoms. It has been reported that a 4% cromolyn sodium cream, applied intravaginally, can prevent local and cutaneous hypersensitivity reactions to seminal fluid (Bosso et al., Allergy Proc. 12(2):113-16, 1991).
Herod et al. briefly mentioned the use of sodium cromoglycate in patients with vulvar intraepithelial neoplasia, a pre-invasive form of vulvar cancer, but did not disclose what formulation of sodium cromoglycate was used, whether the treatment was oral or topical, or the specific results obtained (Br. J. Obstet. Gynaecol. 103:446-52, 1996).
Nedocromil (C.sub.19 H.sub.17 NO.sub.7, 9-ethyl-6,9-dihydro-4,6-dioxo-10-propyl-4H-pyrano[3,2-g]quinoline-2,8-dica rboxylic acid) is another compound known to inhibit the release of mediators from mast cells. Nedocromil has the following structure (II): ##STR2##
The disodium salt of nedocromil (C.sub.19 H.sub.17 NNa.sub.2 O.sub.7, nedocromil sodium) is a water soluble pale yellow powder, which is used as an inhalation therapy for the management of bronchial asthma.